A number of serious metabolic abnormalities have now emerged in HIV disease. These include dramatic redistribution of body fat especially loss of peripheral fat with increased truncal fat, erosion of insulin sensitivity with attendant risk of diabetes and hyperlipidemia all leading to increased risk of coronary artery disease. These three metabolic abnormalities have become a cause for concern. The hypothesis of this proposal is that the cellular mechanism of insulin resistance, and resultant hyperlipidemia, is a defect in insulin signaling like that observed in Type 2 Diabetes Mellitus, and that peripheral fat loss is the result of accelerated programmed cell death or apoposis in peripheral adipose tissue. Specific Aim 1 will assess insulin resistance, body fat distribution and hyperlipidemia, providing the context for correlations to insulin signaling perturbations in muscle and adispose tissue(specific Aim 2) and accelerated adipose tissue apoptosis (Specific Aim 3). Treatment with thiazolidinedione, an insulin sensitizing agent, will be evaluated clinically and at the tissue level (Specific Aim 4).Understanding the perturbations in metabolic control at the tissue level will provide a rational framework for understanding these abnormalities and their mediators, but most importantly, for evaluating potential therapies such as thiazolidinediones.